Inhibition of the lipopolysaccharide-induced stimulation of the members of the MAPK family in human monocytes/macrophages by 4-hydroxynonenal, a product of oxidized omega-6 fatty acids

Am J Pathol. 2008 Oct;173(4):1057-66. doi: 10.2353/ajpath.2008.071150. Epub 2008 Sep 4.

Abstract

The compound 4-hydroxynonenal (4-HNE) is the major aldehyde formed during lipid peroxidation of omega-6-polyunsaturated fatty acids and has been suggested to regulate inflammatory responses because it inhibits tumor necrosis factor (TNF) mRNA production in the human monocytic cell line THP-1. Here we demonstrate that 4-HNE inhibits TNF and interleukin-1beta production in human monocytes in response to lipopolysaccharide. The main action of 4-HNE occurred at the pretranscriptional level; there was no effect on TNF mRNA production or stability when 4-HNE was added after stimulation. The mechanism of action of 4-HNE appears to be downstream of lipopolysaccharide-receptor binding. In the human monocytic MonoMac 6 cell line, 4-HNE caused selective inhibition of the activity of the mitogen-activated protein kinases p38 and ERK1/ERK2, but not JNK. However, in monocytes, the activities of all three kinases were inhibited, suggesting that the effects of 4-HNE were exerted at points upstream of ERK1/ERK2 and JNK as the levels of the phosphorylated kinases were reduced. In contrast, p38 phosphorylation was not inhibited, suggesting that 4-HNE affects kinase activity. 4-HNE also inhibited nuclear factor-kappaB activation in monocytes. In view of the roles of p38, ERK1/ERK2, JNK, and nuclear factor-kappaB in inflammation, the data suggest that 4-HNE, at nontoxic concentrations, has anti-inflammatory properties, most likely through an effect on these signaling molecules, and could lead to the development of novel treatments for inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / pharmacology*
  • Cell Line
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fatty Acids, Omega-6 / metabolism
  • Humans
  • I-kappa B Proteins / metabolism
  • Interleukin-1beta / biosynthesis
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lipopolysaccharides / pharmacology*
  • Macrophages / drug effects*
  • Macrophages / enzymology*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Monocytes / drug effects*
  • Monocytes / enzymology*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Oxidation-Reduction / drug effects
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • RNA Stability / drug effects
  • Transcription, Genetic / drug effects
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Aldehydes
  • Fatty Acids, Omega-6
  • I-kappa B Proteins
  • Interleukin-1beta
  • Lipopolysaccharides
  • NF-kappa B
  • NFKBIA protein, human
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • 4-hydroxy-2-nonenal